The antiviral, biochemical, and pharmacological profile of new chiral p-D- and P-L chiral nucleosides will be determined in vitro and in vivo. The search for new therapies against human immunodeficiency virus (HIV), led to the discovery that certain 2',3'- didehydro-2',3'-dideoxynucleosides (d4N) and their 2'-fluoro analogs are effective antiviral agents. The discovery of a novel cytosine nucleoside, p-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D-D4FC) as a potent anti-human immunodeficiency virus (HIV) agent also led us to synthesize a series of analogs and derivatives of 0-D-D4FC that could be more selective and also possess increased glycosidic bond stability. D-D4FC is a potent and selective inhibitor of HIV-1, HIV-2 and SIV in vitro with a median effective concentration in human peripheral blood mononuclear (PBM) cells of 0.07 uM and no cytotoxicity in human cells up to 100uM D-D4FC and some of the new 2'-fluoro derivatives are also effective in liver hepatocytes against hepatitis B virus (HBV). Surprisingly and in contrast to the toxic L-D4FC enantiomer, D-D4FC had no in vitro toxicity, and had no effect on human bone marrow cells or mitochondria! DMA synthesis. D-D4FC is not cross-resistant with numerous approved and preclinical antiretroviral agents nucleoside analogs, and various protease and non-nucleoside reverse transcriptase inhibitors. It was effective against cloned viruses with single and multiple mutations in the reverse transcriptase region (41L, 65R, 67N, 70R, 103N, 184V, 215Y, 219Q, 21OW). Combination studies in acutely infected human PBM cells indicate that the interaction between D-D4FC and AZT, D4T or Sustiva was not antagonistic. D-D4FC-5'-triphosphate is a potent and selective inhibitor of recombinant HIV-1 RT with an 1050 of 0.1 |jM and no effect on cellular polymerases. D-D4FCTP was a more effective DMAchain terminator than either 3TCTP or L-D4FCTP when either wild-type RT or 184V-mutated RT was used. D-D4FC was also highly effective in a human peripheral blood mononuclear cell SCID-hu HIV-1 mouse model at 60 mg/kg per day when given intraperitoneally for 6 days. Pharmacokinetic studies in rhesus monkeys indicated that the D-D4FC had a terminal oral half-life of 4 hr, was orally bioavailable (F = 48 %), and was primarily cleared unchanged by the kidney. D-D4FC is different from related cytosine nucleosides such as 3TC and (-)-FTC, where the greater potency and lack of cytotoxicity resides with the p-L-enantiomers. D-D4FC has favorable virological and pharmacological properties for advanced preclinical development for HIV infections. Selection in vitro indicated the presence of unique, previously unreported mutations suggesting that this compound has great potential as an antiviral agent. In view of the potent and selective activity against the M184V HIV-1 variants, lack of cross-resistance with other known antiviral agents, dual antiviral activity against HIV-1 and HBV, advanced biochemical and pharmacological studies with D-D4FC and the rich class of active and selective D-2'-F-d4N are proposed for this competitive renewal.